Optimizing Antituberculosis Therapy in Adults With Tuberculous Meningitis

Optimizing Antituberculosis Therapy in Adults With Tuberculous Meningitis Based on N-Acetyltransferase Type 2 Genotyping

The genetically polymorphic N-acetyltransferase type 2 (NAT2) is responsible for isoniazid metabolism, and rapid acetylators were associated with low concentrations of isoniazid based on previous studies. The investigators hypothesize that among rapid acetylators high dose isoniazid would result in lower rates of death and disability in patients with tuberculous meningitis than the rates with the standard regimen. The investigators recruited patients between the ages of 18 and 65 years with newly diagnosed TBM, then NAT2 genotype will be characterized by using High-Resolution Melting Kit (Zeesan Company, Xiamen). Participants with slow or intermediate acetylators will be administered with standard chemotherapy. For participants with rapid acetylators, patients were stratified at study entry according to the modified British Medical Research Council criteria (MRC grade), then randomly assigned in a 1:1 ratio to receive either standard or with high dose isoniazid treatment. All patients received antituberculosis treatment, which consisted of isoniazid (standard dose or high dose), rifampin, pyrazinamide, ethambutol for 3 months, followed by isoniazid, rifampin and ethambutol at the same doses for an additional 9 months. All patients received adjunctive treatment with dexamethasone for the first 6 to 8 weeks of treatment. 338 participants with rapid acetylators were randomly assigned to group B (standard treatment) and group C (high dose isoniazid), respectively. At the same time, 338 participants with slow or intermediate acetylators were recruited to group A (standard treatment). The primary outcome was death or severe disability 12 months after enrollment. Secondary outcome measures were coma-clearance time, fever-clearance time, and difference of laboratory examination (protein concentration, chloride, glucose and white cell counts) of cerebrospinal fluid.

Study Overview

• Status: Recruiting
• Conditions: Tuberculous Meningitis
• Intervention / Treatment: Drug: Isoniazid

Detailed Description

Tuberculous meningitis (TBM) is the most lethal form of tuberculosis, causing death or severe neurologic deficits in more than half of those affected in spite of antituberculosis chemotherapy. Among the first line drugs, isoniazid is the only bactericidal agent that easily crossed blood-brain barrier, achieving concentrations in cerebrospinal fluid (CSF) similar to those in serum. The genetically polymorphic N-acetyltransferase type 2 (NAT2) is responsible for isoniazid metabolism, and individuals can be classified as "rapid acetylators", "intermediate acetylators" or "slow acetylators" based on NAT2 genotyping. Rapid acetylators were associated with low concentrations of isoniazid based on previous studies. The investigators hypothesize that among rapid acetylators high dose isoniazid would result in lower rates of death and disability in patients with tuberculous meningitis than the rates with the standard regimen.

The investigators recruited patients between the ages of 18 and 65 years with newly diagnosed TBM. Patients could not enter the trial if they have been using any other second line antituberculosis drug; if they had received anti-tuberculosis therapy in the past 3 years；if they have positive CSF Gram or India ink stain; if they have received more than 14 days of anti-tuberculosis drugs for the current infection; if they were known or suspected hypersensitivity to or unacceptable side effects from any oral first line antituberculosis drug; if the plasma creatinine concentration was more than the upper limit of the normal range, if the plasma bilirubin concentration was more than 2 times the upper limit of the normal range, or if the plasma alanine aminotransferase level was more than three times the upper limit of the normal range; if they were known or suspected pregnancy; if they were known or suspected isoniazid and/or rifampin resistant; if they were lack of consent； if they were any participant for whom investigators judge this study is not appropriated.

Participants will be recruited from four sites in China, including Beijing Chest Hospital affiliated to Capital Medical University, Zunyi Medical College affiliated Hospital, Jiangxi Provincial Chest Hospital and Jiamusi Infectious Disease Hospital. All hospitals serve the local community and act as tertiary referral centers for patients with severe tuberculosis or infectious diseases in China.

Written informed consent to participate in the study was obtained from all patients. Then NAT2 genotype will be characterized by using High-Resolution Melting Kit (Zeesan Company, Xiamen). Participants with slow or intermediate acetylators will be administered with standard chemotherapy (3 months HRZE followed by 9 months HRE). For participants with rapid acetylators, patients were stratified at study entry according to the modified British Medical Research Council criteria (MRC grade), then randomly assigned in a 1:1 ratio to receive either standard or high dose isoniazid treatment.

All patients received antituberculosis treatment, which consisted of isoniazid (300 mg for standard treatment and 900 mg for high dose treatment), rifampin (450 mg for weight no more than 50 kg, 600 mg for weight more than 50 kg), pyrazinamide (1500 mg for weight no more than 50 kg, 1750 mg for weight more than 50 kg), ethambutol (750 mg for weight no more than 50 kg, 1000 mg for weight more than 50 kg) for 3 months, followed by isoniazid, rifampin and ethambutol at the same doses for an additional 9 months. All patients received adjunctive treatment with dexamethasone for the first 6 to 8 weeks of treatment, as recommend by British Infection Society.

338 participants with rapid acetylators will be randomly assigned to group B (standard treatment) and group C (high dose isoniazid), respectively. The calculation assumes an overall mortality and severe disability of 50% vs. 70 % in the two arms, a power of 80% and a two-sided significance level of 5%. Randomization ration is 1:1. At the same time, 338 participants with slow or intermediate acetylators were recruited to group A (standard treatment).

The primary outcome was death or severe disability 12 months after enrollment. Secondary outcome measures were coma-clearance time, fever-clearance time, and difference of CSF laboratory examination (protein concentration, chloride, glucose and white cell counts) of cerebrospinal fluid after 3 months treatment.

• Study Type: Interventional
• Enrollment (Anticipated): 676
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hongfei Duan, MD; Phone Number: 13520728402; Email: duanhongfei@hotmail.com
• Study Contact Backup: Name: Lingling Shao, Master; Phone Number: 15810187170; Email: shaolinglinglky@163.com

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Beijing Chest Hospital affiliated to Capital Medical University
    • Contact: Hongfei Duan
  • Jiamusi, China
    • Recruiting
    • Jiamusi Infectious Disease Hospital
    • Contact: Chao Qiu
  • Nanchang, China
    • Recruiting
    • Jiangxi provincial chest hospital
    • Contact: Qilong Zhang
  • Zunyi, China
    • Recruiting
    • Zunyi Medical College affiliated Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 to 65 years of age;
• Clinical diagnosis of TBM;
• Able and willing to provide informed consent to participate in the study.

Exclusion Criteria:

• Using any other second line antituberculosis drug;
• Received anti-tuberculosis therapy in the past 3 years；
• Positive CSF Gram or India ink stain;
• Received more than 14 days of anti-tuberculosis drugs for the current infection;
• Known or suspected hypersensitivity to or unacceptable side effects from any oral first line antituberculosis drug;
• Plasma creatinine concentration was more than the upper limit of the normal range, or the plasma bilirubin concentration was more than 2 times the upper limit of the normal range, or the plasma alanine aminotransferase level was more than three times the upper limit of the normal range;
• Known or suspected pregnancy;
• Known or suspected isoniazid and/or rifampin resistant;
• Lack of consent；
• Any participant for whom investigators judge this study is not appropriate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard INH for Non-rapid acetylators; Participant with slow or intermediate acetylators(one of N-Acetyltransferase Type 2 Genotype) administered with standard chemotherapy (3 months HRZE followed by 9 months HRE with standard dose isoniazid)	Drug: Isoniazid; standard dose isoniazid or high dose isoniazid for participants with rapid acetylators
Active Comparator: Standard INH for rapid acetylators; Participant with rapid acetylators(one of N-Acetyltransferase Type 2 Genotype) administered with standard chemotherapy (3 months HRZE followed by 9 months HRE with standard dose isoniazid )	Drug: Isoniazid; standard dose isoniazid or high dose isoniazid for participants with rapid acetylators
Experimental: High dose INH for rapid acetylators; Participant with rapid acetylators(one of N-Acetyltransferase Type 2 Genotype) administered with high dose isonized treatment (3 months HRZE followed by 9 months HRE with high dose isoniazid)	Drug: Isoniazid; standard dose isoniazid or high dose isoniazid for participants with rapid acetylators

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with death or severe disability	Number of Participants with death or severe disability 12 months after enrollment	up to 12 months after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
days for coma-clearance time	days for coma-clearance time through study completion	through study completion,up to 1 year
days for fever-clearance time	days for fever-clearance time through study completion	through study completion,up to 1 year
difference of CSF protein concentration	difference of CSF protein concentration (g/L)	3 months after enrollment
difference of CSF glucose concentration	difference of CSF glucose concentration (mmol/L)	3 months after enrollment
difference of CSF white cell counts	difference of CSF white cell counts (per milliliter)	3 months after enrollment
difference of CSF chloride concentration	difference of CSF chloride concentration (mmol/L)	3 months after enrollment

Collaborators and Investigators

• Sponsor: Beijing Chest Hospital
• Investigators: Principal Investigator: Hongfei Duan, MD, Beijing Chest Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2019
• Primary Completion (Anticipated): December 31, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: November 19, 2018
• First Submitted That Met QC Criteria: December 24, 2018
• First Posted (Actual): December 27, 2018

Study Record Updates

• Last Update Posted (Actual): February 1, 2021
• Last Update Submitted That Met QC Criteria: January 28, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: treatment; Tuberculous Meningitis; N-Acetyltransferase Type 2 Genotype
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Tuberculosis; Meningitis; Tuberculosis, Meningeal; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Antitubercular Agents; Fatty Acid Synthesis Inhibitors; Isoniazid
• Other Study ID Numbers: 2018ZX10302302-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No